Randomized placebo-controlled trial of the effects of aspirin on dementia and cognitive decline

Abstract

Objective: To determine the effect of low-dose aspirin vs placebo on incident all-cause dementia, incident Alzheimer disease (AD), mild cognitive impairment (MCI), and cognitive decline in older individuals.

Methods: Aspirin in Reducing Events in the Elderly (ASPREE) was a double-blind, placebo-controlled trial of low-dose aspirin. In the United States and Australia, community-dwelling individuals aged ≥70 years (US minorities ≥65 years) and free of cardiovascular disease, physical disability, and diagnosed dementia were enrolled. Participants were randomized 1:1-100 mg daily aspirin or placebo. The Modified Mini-Mental State Examination, Hopkins Verbal Learning Test-Revised, Symbol Digit Modalities Test, and Controlled Oral Word Association Test assessed cognition at baseline and over follow-up. Additional cognitive testing was performed in participants with suspected dementia ("trigger") based on within-study assessments or clinical history. Dementia was adjudicated according to DSM-IV criteria. National Institute on Aging-Alzheimer's Association criteria were used for AD and MCI subclassification.

Results: A total of 19,114 participants were followed over a median 4.7 years and 964 triggered further dementia assessments. There were 575 adjudicated dementia cases, and 41% were classified as clinically probable AD. There was no substantial difference in the risk of all dementia triggers (hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.91-1.17), probable AD (HR, 0.96; 95% CI, 0.74-1.24), or MCI (HR, 1.12; 95% CI, 0.92-1.37) between aspirin and placebo. Cognitive change over time was similar in the aspirin and placebo groups.

Conclusions: There was no evidence that aspirin was effective in reducing risk of dementia, MCI, or cognitive decline. Follow-up of these outcomes after initial exposure is ongoing.

Classification of evidence: This study provides Class II evidence that for healthy older individuals, low-dose aspirin does not significantly reduce the incidence of dementia, probable AD, MCI, or cognitive decline.

Clinicaltrialsgov identifier: NCT01038583.

Figure 1. Consolidated Standards of Reporting Trials (CONSORT) flow diagram of participants in the Aspirin in Reducing Events in the Elderly (ASPREE) trial

All randomized participants were included in the final analysis. For participants who withdrew from the trial or died, all information up to the point of withdrawal/death was included in the analysis.

Figure 2. Cumulative incidence of dementia subtype

Cumulative incidences of all events of clinically probable Alzheimer disease (AD) and possible AD that were observed during the trial. CI = confidence interval.

Figure 3. Forest plot for adjudicated incidence of dementia (all-cause) in prespecified subgroups

Arrows indicate that the 95% confidence intervals (CIs) were beyond the scale. Other ethnic/racial group included individuals who were not Hispanic but who did not state another race or ethnic group (18), or any other category with fewer than 200 participants overall. This included Aboriginal or Torres Strait Islander (12 participants), Native American (6), multiple races or ethnic groups (64), and Native Hawaiian or Pacific Islander (11). The presence of diabetes was based on participants’ report of diabetes mellitus or a fasting glucose level of at least 126 mg/dL (≥7 mmol/L) or receipt of treatment for diabetes. Hypertension was defined as treatment for high blood pressure or a blood pressure of greater than 140/90 mm Hg at trial entry. Dyslipidemia was defined as the receipt of cholesterol-lowering medication or as a serum cholesterol level of at least 212 mg/dL (≥5.5 mmol/L) in Australia and at least 240 mg/dL (≥6.2 mmol/L) in the United States or as a low-density lipoprotein level of more than 160 mg/dL (>4.1 mmol/L). Previous regular aspirin use was defined according to participant-reported regular use of aspirin immediately before the first baseline visit, with a 1-month washout period before randomization. Frailty was categorized on the basis of the adapted Fried frailty criteria, which included body weight, strength, exhaustion, walking speed, and physical activity. The category of prefrail included participants who met 1 or 2 criteria, and the category of frail included those who met 3 or more criteria. Body mass index is the weight in kilograms divided by the square of the height in meters.

Figure 4. Cumulative incidence of mild cognitive impairment (MCI) and cognitive decline

Cumulative incidences of all events of incident MCI and cognitive decline that were observed during the trial. CI = confidence interval.